Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro

Anti-neoplastic potential of calorie restriction or ligand-induced activation of peroxisome proliferator activated receptors (PP ARs) has been demonstrated in multiple studies; however, mechanism(s) by which tumor cells respond to these stimuli remain to be elucidated. One of the potent agonists of PPAR alpha, fenofibrate, is a commonly used lipid-lowering drug with low systemic toxicity. Fenofibrate-induced PPAR alpha transcriptional activity is expected to shift energy metabolism from glycolysis to fatty acid beta-oxidation, which in the long-term, could target weak metabolic points of glycolysis-dependent glioblastoma cells. The results of this study demonstrate that 25 mu M fenofibrate can effectively repress malignant growth of primary glial tumor cells and glioblastoma cell lines. This cytostatic action involves G(1) arrest accompanied by only a marginal level of apoptotic cell death. Although the cells treated with 25 mu M fenofibrate remain arrested, the cells treated with 50 mu M fenofibrate undergo massive apoptosis, which starts after 72 h of the treatment. This delayed apoptotic event was preceded by FoxO3A nuclear accumulation, FoxO3A phosphorylation on serine residue 413, its elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. siRNA-mediated inhibition of FoxO3A attenuated fenofibrate-induced apoptosis, indicating a direct involvement of this transcription factor in the fenofibrate action against glioblastoma. These properties of fenofibrate, coupled with its low systemic toxicity, make it a good candidate in support of conventional therapies against glial tumors.